Farmacogenômica das fluoropirimidinas no tratamento oncológico personalizado
Recently, cancer has become an obvious public health problem worldwide. The Fluoropyrimidine-based regimen has been the most widely used chemotherapy regimen worldwide in several types of solid tumors, including gastric and colorectal cancer. Of the total number of patients treated with 5-Fluorourac...
| Autor principal: | FERNANDES, Marianne Rodrigues |
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| Grau: | Tese |
| Idioma: | por |
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Universidade Federal do Pará
2017
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http://repositorio.ufpa.br/jspui/handle/2011/8940 |
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ir-2011-89402024-09-18T15:39:28Z Farmacogenômica das fluoropirimidinas no tratamento oncológico personalizado FERNANDES, Marianne Rodrigues BURBANO, Rommel Mario Rodriguéz http://lattes.cnpq.br/4362051219348099 Medicina personalizada Oncologia Farmacogenética Farmacogenômica Câncer gástrico Câncer colorretal Fluoropirimidina CNPQ::CIENCIAS DA SAUDE::MEDICINA::CLINICA MEDICA::CANCEROLOGIA CNPQ::CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICA Recently, cancer has become an obvious public health problem worldwide. The Fluoropyrimidine-based regimen has been the most widely used chemotherapy regimen worldwide in several types of solid tumors, including gastric and colorectal cancer. Of the total number of patients treated with 5-Fluorouracil (5-FU), 10-40% have severe toxicities, which usually result in prolonged and costly hospitalizations. The principle of personalized medicine is to study responses to medications based on individual genomic information. The high degree of miscegenation is a challenge for the worldwide implementation of personalized medicine in clinical practice. Many studies in the specialized literature have reported the influence of pharmacogenomic markers in mixed populations such as the Brazilian population. The aim of this study was to investigate the pharmacogenomic variability of different biomarkers in pharmacogenes involved in the metabolism pathway of Fluoropyrimidines in patients with gastric cancer or colorectal cancer, which are sub-strutured according to response and toxicity to treatment. To perform the research we used 216 patients with colorectal or gastric cancer who received 5-FU chemotherapy treatment. We investigated 33 genetic polymorphisms in 17 pharmacogens (ABCB1, ABCC2, ABCC4, ABCG2, CYP2A6, DPYD, FPSG, ITGB5, MTHFR, SLC22A7, SLC29A1, TP53, TYMS, UMPS, GGH, RRM1, TYMP) involved in the metabolism pathway of fluoropyrimidines. Our results showed that 77.3% of the patients presented some type of toxicity related to 5-FU treatment, of which 22% presented severe toxicities classified in grade 3 and 4. Death occurred in 23 patients, where three cases were related to toxicity and four cases with tumor progression and chemotherapeutic toxicity. Population substructuration was not influential in the association results for pharmacogenetic polymorphisms with the use of 5-FU. The FPGS gene (rs4451422) was shown to be significant in association with overall toxicity (p = 0.0052; OR 0.32) and toxicity events (p = 0.0004; OR 0.22). The ABCC4 gene (rs148551) had a significant association with the clinical response (p = 0.0056; OR 0.28). The SLC29A1 gene (rs760370) was shown to be significant for grade 3 and 4 toxicities (p = 0.0033; OR 4.73). In conclusion, due to the high degree of miscegenation in the Brazilian population, and particularly in the North of Brazil, the generated 5-FU pharmacogenomics data are particularly unique when compared to the homogenous populations investigated to date. The ABCC4, FPGS and SLC29A1 genes have been shown to be important biomarkers predictive of personalized medicine therapy using 5-FU. CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico FAPESPA - Fundação Amazônia de Amparo a Estudos e Pesquisas Nas últimas décadas, o câncer se tornou um evidente problema de saúde pública mundial. O esquema terapêutico com base em Fluoropirimidinas tem sido a conduta quimioterápica mais utilizada em todo o mundo em vários tipos de tumores sólidos, incluindo câncer gástrico e colorrectal. Do total de pacientes tratados com 5-Fluorouracil (5-FU), de 10-40% apresentam toxicidades severas, em geral estes casos resultam em hospitalizações prolongadas e onerosas. O principio da medicina personalizada consiste em estudar as respostas a medicamentos baseados na informação genômica individual. O elevado grau de miscigenação é um desafio para a implementação mundial da medicina personalizada na prática clínica. Poucos estudos na literatura especializada relataram a influência de marcadores farmacogenômicos em populações miscigenadas como a população brasileira. O objetivo deste estudo foi investigar a variabilidade farmacogenômica de diferentes biomarcadores em farmacogenes envolvidos na via de metabolismo das Fluoropirimidinas em pacientes com câncer gástrico ou câncer colorrectal, subestuturados de acordo com a resposta e toxicidade ao tratamento. Para a realização da investigação utilizamos 216 pacientes com câncer colorretal ou gástrico que receberam tratamento quimioterápico a base de 5-FU. Foram investigados 33 polimorfismos genéticos em 17 farmacogenes (ABCB1, ABCC2; ABCC4; ABCG2, CYP2A6, DPYD, FPSG, ITGB5, MTHFR, SLC22A7, SLC29A1, TP53, TYMS, UMPS, GGH, RRM1, TYMP) envolvidos na via de metabolizacão das fluoropirimidinas. Nossos resultados demonstraram que 77.3% dos pacientes apresentaram algum tipo de toxicidade relacionada ao tratamento com 5-FU e destes, 22% apresentaram toxicidades severas classificadas em grau 3 e 4. O óbito ocorreu em 23 pacientes, onde três casos foram relacionados à toxicidade e quatro casos com a progressão tumoral e toxicidade quimioterápica. O subestruturamento populacional não foi influente nos resultados de associação para os polimorfismos farmacogenéticos com o uso de 5-FU. O gene FPGS (rs4451422) mostrou-se significativo em associação com a toxicidade geral (p=0,0052; OR 0,32) e com eventos de toxicidades (p=0,0004; OR 0,22). O gene ABCC4 (rs148551) apresentou associação significativa para a resposta clínica (p=0,0056; OR 0,28). O gene SLC29A1 (rs760370) demonstrouse significativo para toxicidades de grau 3 e 4 (p=0,0033; OR 4,73). Em conclusão, devido ao elevado grau de miscigenação da população brasileira, e particularmente do Norte do Brasil, os dados gerados de farmacogenômica do 5- FU são particularmente únicos se comparados com as populações homogêneas investigadas ate o presente. Os genes ABCC4, FPGS e SLC29A1 demonstraram ser importantes biomarcadores preditivos para a medicina personalizada da terapia com uso de 5-FU. 2017-08-01T14:23:50Z 2017-08-01T14:23:50Z 2016-12-29 Tese FERNANDES, Marianne Rodrigues. Farmacogenômica das fluoropirimidinas no tratamento oncológico personalizado. 2016. 86 f. Tese (Doutorado) – Universidade Federal do Pará, Instituto de Ciências Biológicas, Belém, 2016. Programa de Pós-Graduação em Genética e Biologia Molecular. http://repositorio.ufpa.br/jspui/handle/2011/8940 por Acesso Aberto application/pdf Universidade Federal do Pará Brasil Instituto de Ciências Biológicas UFPA Programa de Pós-Graduação em Genética e Biologia Molecular |
| institution |
Repositório Institucional - Universidade Federal do Pará |
| collection |
RI-UFPA |
| language |
por |
| topic |
Medicina personalizada Oncologia Farmacogenética Farmacogenômica Câncer gástrico Câncer colorretal Fluoropirimidina CNPQ::CIENCIAS DA SAUDE::MEDICINA::CLINICA MEDICA::CANCEROLOGIA CNPQ::CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICA |
| spellingShingle |
Medicina personalizada Oncologia Farmacogenética Farmacogenômica Câncer gástrico Câncer colorretal Fluoropirimidina CNPQ::CIENCIAS DA SAUDE::MEDICINA::CLINICA MEDICA::CANCEROLOGIA CNPQ::CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICA FERNANDES, Marianne Rodrigues Farmacogenômica das fluoropirimidinas no tratamento oncológico personalizado |
| topic_facet |
Medicina personalizada Oncologia Farmacogenética Farmacogenômica Câncer gástrico Câncer colorretal Fluoropirimidina CNPQ::CIENCIAS DA SAUDE::MEDICINA::CLINICA MEDICA::CANCEROLOGIA CNPQ::CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICA |
| description |
Recently, cancer has become an obvious public health problem worldwide. The Fluoropyrimidine-based regimen has been the most widely used chemotherapy regimen worldwide in several types of solid tumors, including gastric and colorectal cancer. Of the total number of patients treated with 5-Fluorouracil (5-FU), 10-40% have severe toxicities, which usually result in prolonged and costly hospitalizations. The principle of personalized medicine is to study responses to medications based on individual genomic information. The high degree of miscegenation is a challenge for the worldwide implementation of personalized medicine in clinical practice. Many studies in the specialized literature have reported the influence of pharmacogenomic markers in mixed populations such as the Brazilian population. The aim of this study was to investigate the pharmacogenomic variability of different biomarkers in pharmacogenes involved in the metabolism pathway of Fluoropyrimidines in patients with gastric cancer or colorectal cancer, which are sub-strutured according to response and toxicity to treatment. To perform the research we used 216 patients with colorectal or gastric cancer who received 5-FU chemotherapy treatment. We investigated 33 genetic polymorphisms in 17 pharmacogens (ABCB1, ABCC2, ABCC4, ABCG2, CYP2A6, DPYD, FPSG, ITGB5, MTHFR, SLC22A7, SLC29A1, TP53, TYMS, UMPS, GGH, RRM1, TYMP) involved in the metabolism pathway of fluoropyrimidines. Our results showed that 77.3% of the patients presented some type of toxicity related to 5-FU treatment, of which 22% presented severe toxicities classified in grade 3 and 4. Death occurred in 23 patients, where three cases were related to toxicity and four cases with tumor progression and chemotherapeutic toxicity. Population substructuration was not influential in the association results for pharmacogenetic polymorphisms with the use of 5-FU. The FPGS gene (rs4451422) was shown to be significant in association with overall toxicity (p = 0.0052; OR 0.32) and toxicity events (p = 0.0004; OR 0.22). The ABCC4 gene (rs148551) had a significant association with the clinical response (p = 0.0056; OR 0.28). The SLC29A1 gene (rs760370) was shown to be significant for grade 3 and 4 toxicities (p = 0.0033; OR 4.73). In conclusion, due to the high degree of miscegenation in the Brazilian population, and particularly in the North of Brazil, the generated 5-FU pharmacogenomics data are particularly unique when compared to the homogenous populations investigated to date. The ABCC4, FPGS and SLC29A1 genes have been shown to be important biomarkers predictive of personalized medicine therapy using 5-FU. |
| author_additional |
BURBANO, Rommel Mario Rodriguéz |
| author_additionalStr |
BURBANO, Rommel Mario Rodriguéz |
| format |
Tese |
| author |
FERNANDES, Marianne Rodrigues |
| title |
Farmacogenômica das fluoropirimidinas no tratamento oncológico personalizado |
| title_short |
Farmacogenômica das fluoropirimidinas no tratamento oncológico personalizado |
| title_full |
Farmacogenômica das fluoropirimidinas no tratamento oncológico personalizado |
| title_fullStr |
Farmacogenômica das fluoropirimidinas no tratamento oncológico personalizado |
| title_full_unstemmed |
Farmacogenômica das fluoropirimidinas no tratamento oncológico personalizado |
| title_sort |
farmacogenômica das fluoropirimidinas no tratamento oncológico personalizado |
| publisher |
Universidade Federal do Pará |
| publishDate |
2017 |
| url |
http://repositorio.ufpa.br/jspui/handle/2011/8940 |
| _version_ |
1811330132151894016 |
| score |
11.675088 |